CN115160293A - 锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用 - Google Patents
锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用 Download PDFInfo
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Abstract
本发明涉及放射性药物化学和临床核医学技术领域,具体涉及锝‑99m标记含L‑脯氨酸修饰的谷氨酸‑脲衍生物及制备方法和应用。将所述含L‑脯氨酸修饰的谷氨酸‑脲衍生物用99mTc标记得到的放射性制剂,在肿瘤中具有高摄取,同时肿瘤/非靶比值好,与前列腺特异性膜抗原特异性结合,可用作前列腺癌诊断的有推广应用价值的新型肿瘤放射性药物。
Description
技术领域
本发明涉及放射性药物和核医学领域,具体涉及锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用。
背景技术
全球范围内,前列腺癌是男性第二常见的癌症。随着人口老龄化加剧以及人们生活方式的改变,近年来国内外前列腺癌群体不断扩大。转移、复发和去势抵抗是导致前列腺癌患者死亡的主要原因。预后效果与肿瘤的分期密切相关,因此前列腺癌的早期诊断和复发病灶探测对降低前列腺癌的死亡率至关重要。前列腺特异性膜抗原(prostate-specificmembrane antigen,PSMA)高度特异性表达于前列腺癌细胞表面,且与肿瘤的恶化程度和癌症分期呈正相关,使其成为前列腺癌分子影像诊断及靶向治疗领域中优秀的靶点。相较于传统的前列腺癌诊疗方法,以放射性核素标记的PSMA小分子抑制剂为代表的靶向试剂,已发挥出独特优势并展现出广阔的临床应用前景。
近期研究表明,含有谷氨酸-脲(Glu-urea)单元的小分子抑制剂表现出与前列腺癌细胞表面的PSMA的高亲和力、特异性。借助放射性核素标记含谷氨酸-脲单元的PSMA抑制剂可为前列腺癌精准分期、复发病灶的精准定位提供有效成像工具,成为国际放射性药物的研究热点。但由于PSMA在近端肾小管中也有一定程度的表达,该类放射性核素标记的PSMA抑制剂的肾脏摄取普遍较高,对病人肾脏带来辐射损伤是亟待解决的问题。99mTc作为临床应用最广泛的SPECT显像核素,具有合适的核素性质,可由99Mo/99mTc发生器淋洗获得,且99mTc标记的药物便于药盒化生产,易于临床推广使用,因此研制靶向PSMA的用于前列腺癌特异性诊断的新型99mTc放射性药物具有重要的现实意义。
连接剂(linker)连接了靶向基团和与放射性核素相连的螯合基团,对于调节放射性药物的药效和药代动力学发挥重要作用。本发明使用L-脯氨酸作为连接剂,拟通过改善配合物的药代动力学性质,一方面保持配合物在肿瘤中高摄取,另一方面减少配合物在肾脏中的摄取,从而降低对肾脏的辐射损伤。肼基尼古酰胺(HYNIC)是99mTc标记的放射性药物研究中常用的一种双功能连接剂。基于以上背景,本发明通过合成含L-脯氨酸和肼基尼古酰胺基的谷氨酸-脲衍生物,在其他共配体的参与下,将其进行99mTc标记来探求新型特异性靶向PSMA的肿瘤放射性药物,具有重要的科学意义和广阔的临床应用前景。
发明内容
本发明提供了一种锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用,该衍生物稳定性好,制备简便,进行放射性标记后用于前列腺肿瘤诊疗,肿瘤摄取高且靶/非靶比值好,在肿瘤诊疗领域具有重要的科学意义和应用前景。
具体地,本发明提供以下技术方案:
含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用,所述的结构式为(I):
由该衍生物制备得到的相应99mTc配合物与PSMA特异性结合,在非靶器官中有很低的摄取,有高的肿瘤摄取值、肿瘤/血和肿瘤/肌肉比值,能够针对前列腺肿瘤诊疗取得很好的效果。本发明还提供一种放射性制剂,所述放射性制剂包含用放射性核素标记的上述含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用。
优选的,上述放射性制剂中,所述放射性核素部分为金属放射性核素。
优选的,上述放射性制剂中,所述金属放射性核素为99mTc、99Tc、94mTc、94Tc、52Mn、186Re或188Re。
最优选的,上述放射性制剂中,所述放射性核素为99mTc,所述放射性制剂的结构式为(II):
式中:M为99mTc形成稳定99mTc配合物时的共配体组分,为N-三(羟甲基)甲基甘氨酸(Tricine)和乙二胺-N,N'-二乙酸(EDDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠(TPPTS)、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯-3-磺酸钠(TPPMS)、N-三(羟甲基)甲基甘氨酸(Tricine)和2-(吡啶-4-基)乙酸(PA)、N-三(羟甲基)甲基甘氨酸(Tricine)和烟酸(NIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和异烟酸(ISONIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,5-吡啶二羧酸(PDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和3-吡啶磺酸(PSA)。
本发明还提供上述放射性制剂在前列腺肿瘤诊断领域和/或前列腺肿瘤治疗领域中的应用。本发明的有益效果在于:本发明提供一种含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用,将其用放射性核素标记得到的放射性制剂,在前列腺肿瘤中具有高摄取,同时肿瘤/非靶比值好,是一种有推广意义的新型肿瘤放射性药物。
具体实施方式
本发明提供了一种锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用,在一种优选的实施方式中,本发明提供结构通式为99mTc-GLPH-M的放射性制剂:
式中:M为99mTc形成稳定99mTc配合物时的共配体组分,为N-三(羟甲基)甲基甘氨酸(Tricine)和乙二胺-N,N'-二乙酸(EDDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠(TPPTS)、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯-3-磺酸钠(TPPMS)、N-三(羟甲基)甲基甘氨酸(Tricine)和2-(吡啶-4-基)乙酸(PA)、N-三(羟甲基)甲基甘氨酸(Tricine)和烟酸(NIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和异烟酸(ISONIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,5-吡啶二羧酸(PDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和3-吡啶磺酸(PSA)。
其制备步骤如下:
a.配体GLPH的合成
取25mL三口圆底瓶,加入化合物1和二氯甲烷搅拌溶解,再加入化合物2和三乙胺,室温反应12h后,旋转蒸发除去溶剂,粗产物经柱层析纯化得到化合物3。将化合物3溶于二氯甲烷和三氟乙酸的混合溶液(体积比为1:1),室温搅拌8h,旋转蒸发除去溶剂,即得到配体GLPH。
具体合成路线为:
b.99mTc-GLPH-M配合物的制备
将GLPH和Tricine溶于生理盐水中,加入EDDA或TPPTS或TPPMS或PA或NIC或ISONIC或PDA或PSA,加入SnCl2·2H2O,调节溶液pH值约5.0-7.0,然后向其中加入新鲜淋洗的Na99mTcO4溶液,100℃下反应20-30min后即得到所述的99mTc-GLPH-M配合物。
通过上述方法制备的99mTc-GLPH-M配合物的放射化学纯度大于90%,为亲水性物质,体外稳定性良好。99mTc-GLPH-M配合物在肾脏中有特异性摄取且能被抑制剂显著抑制,在荷瘤小鼠肿瘤部位摄取和肿瘤/非靶比值较好,肿瘤摄取也能被抑制剂显著抑制,是有推广应用价值的新型靶向PSMA的肿瘤放射性药物。
以下实施例用于说明本发明,但不用来限制本发明的范围。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。
具体实施方式
下面通过实施例详述本发明:锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用,可用于靶向PSMA的SPECT/CT显像,其结构通式为99mTc-GLPH-M。
式中:M为99mTc形成稳定99mTc配合物时的共配体组分,为N-三(羟甲基)甲基甘氨酸(Tricine)和乙二胺-N,N'-二乙酸(EDDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠(TPPTS)、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯-3-磺酸钠(TPPMS)、N-三(羟甲基)甲基甘氨酸(Tricine)和2-(吡啶-4-基)乙酸(PA)、N-三(羟甲基)甲基甘氨酸(Tricine)和烟酸(NIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和异烟酸(ISONIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,5-吡啶二羧酸(PDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和3-吡啶磺酸(PSA)等。
99mTc-GLPH-M的制备方法如下,但是并不仅限制于举例说明的配合物:
a.配体GLPH的合成
取25mL三口圆底瓶,加入130.7mg(0.268mmol)化合物1和10mL二氯甲烷搅拌溶解,再加入100.0mg(0.223mmol)化合物2和101μL(0.731mmol)三乙胺,室温反应12h后,旋转蒸发除去溶剂,粗产物经柱层析纯化(二氯甲烷/甲醇=10:1,Rf=0.4)得到化合物3,产率为43.7%。将化合物3溶于二氯甲烷和三氟乙酸的混合溶液(体积比为1:1),室温搅拌8h,旋转蒸发除去溶剂,即为配体GLPH。1H-NMR(600MHz,CD3OD)δ(ppm):8.36–8.25(m,1H),8.04(d,J=9.3Hz,1H),6.94(d,J=9.3Hz,1H),4.49(t,J=6.8Hz,1H),4.27(dd,J=8.2,4.7Hz,1H),4.23(dd,J=8.5,4.3Hz,1H),3.70(dd,J=15.0,7.7Hz,1H),3.64(dd,J=9.6,4.7Hz,1H),3.37–3.31(m,1H),3.15(dd,J=12.7,6.5Hz,1H),2.34–2.30(m,3H),2.08–2.03(m,1H),1.97–1.90(m,2H),1.79(dd,J=14.4,5.5Hz,1H),1.68–1.65(m,1H),1.57–1.53(m,2H),1.44(d,J=5.5Hz,2H),1.32–1.24(m,2H).HR-MS(ESI)for C23H34N7O9[M+H]+:found552.2417,calcd552.2412.
b.99mTc-GLPH-EDDA配合物的制备
取10μg配体GLPH,250μL乙二胺-N,N'-二乙酸(EDDA,40mg/mL,0.2mol/L NaOH),20mg N-三(羟甲基)甲基甘氨酸(Tricine),100μg SnCl2·2H2O,20mg甘露醇和0.5mL PBS(0.2mol/L,pH=6.0),加入150μL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-EDDA。
c.99mTc-GLPH-TPPTS配合物的制备
取10μg配体GLPH,1mg N-三(羟甲基)甲基甘氨酸(Tricine),2mg三苯基膦三间磺酸钠(TPPTS),100μg SnCl2·2H2O,20mg甘露醇和0.5mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.4mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应30min,即得目标配合物99mTc-GLPH-TPPTS。
d.99mTc-GLPH-TPPMS配合物的制备
取10μg配体GLPH,1mg N-三(羟甲基)甲基甘氨酸(Tricine),2mg二苯基膦苯-3-磺酸钠(TPPMS),30μg SnCl2·2H2O,0.4mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应30min,即得目标配合物99mTc-GLPH-TPPMS。
e.99mTc-GLPH-PA配合物的制备
取10μg配体GLPH,5mg N-三(羟甲基)甲基甘氨酸(Tricine),4mg 2-(吡啶-4-基)乙酸(PA),30μg SnCl2·2H2O,0.4mL PBS(0.2mol/L,pH=6.5),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-PA。
f.99mTc-GLPH-NIC配合物的制备
取10μg配体GLPH,5mg N-三(羟甲基)甲基甘氨酸(Tricine),2mg烟酸(NIC),30μgSnCl2·2H2O,0.4mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-NIC。
g.99mTc-GLPH-ISONIC配合物的制备
取10μg配体GLPH,5mg N-三(羟甲基)甲基甘氨酸(Tricine),4mg异烟酸(ISONIC),30μg SnCl2·2H2O,0.4mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-ISONIC。
h.99mTc-GLPH-PDA配合物的制备
取10μg配体GLPH,5mg N-三(羟甲基)甲基甘氨酸(Tricine),4mg 3,5-吡啶二羧酸(PDA),30μg SnCl2·2H2O,0.4mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-PDA。
i.99mTc-GLPH-PSA配合物的制备
取10μg配体GLPH,5mg N-三(羟甲基)甲基甘氨酸(Tricine),4mg 3-吡啶磺酸(PSA),30μg SnCl2·2H2O,0.4mL琥珀酸盐缓冲液(0.5mol/L,pH=5.0),加入0.5mL无菌注射水溶解,然后加入0.1mL Na99mTcO4淋洗液,沸水浴反应20min,即得目标配合物99mTc-GLPH-PSA。
实验表明,配合物99mTc-GLPH-M的性能如下:
1.配合物的鉴定
薄层层析色谱(TLC)鉴定:
展开体系为:聚酰胺薄膜作为支持体,醋酸铵(1mol/L)/甲醇=2:1(V/V)作为展开剂,在该体系下,各放射性组分的Rf值如下表所示。
表1配合物各组分的层析结果(Rf值)
由上述层析鉴定所测得的标记物的放射化学纯度大于90%。
2.配合物的脂水分配系数的测定
取0.8mL正辛醇和0.7mL pH=7.4(0.025mol/L)的磷酸盐缓冲液于2mL离心试管中,在离心试管中加入0.1mL配合物溶液,盖上塞子,涡旋充分混匀,离心5min(3000r/min)。分别从有机相和水相中取出0.1mL,测定两相的放射性计数,并计算log P值(P=有机相的放射性活度/水相的放射性活度)。配合物的脂水分配系数结果如下表所示:
表2配合物的脂水分配系数结果
脂水分配系数结果表明,配合物均为水溶性物质。
3.配合物的体外稳定性测定
将标记好的配合物分别在室温下和在37℃小鼠血清中放置6小时后测定其放射化学纯度,实验结果表明配合物在室温下和在37℃小鼠血清中放置6小时后放射化学纯度均大于90%,说明其体外稳定性好。
4.配合物在小鼠中生物分布实验
为了验证配合物是特异性靶向PSMA的肿瘤显像剂,用PSMA抑制剂ZJ-43进行了抑制实验。提前30min给每只正常昆明雄性小鼠的尾静脉注射500μg ZJ-43,然后再注射0.1mL配合物溶液(0.185MBq,15pmol)。给药2h后处死小鼠,取其肾脏、心、肺、血、肌肉等组织和脏器,擦净后称重并利用γ-Counter计数器测其放射性计数,计算肾脏的每克百分注射剂量(%ID/g)。生物分布结果见表3-10。
表3 99mTc-GLPH-EDDA在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表4 99mTc-GLPH-TPPTS在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表5 99mTc-GLPH-TPPMS在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表6 99mTc-GLPH-PA在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表7 99mTc-GLPH-NIC在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表8 99mTc-GLPH-ISONIC在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表9 99mTc-GLPH-PDA在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
表10 99mTc-GLPH-PSA在正常昆明雄性小鼠中生物分布结果(2h p.i.,n=5,%ID/g)
从表3-10可以看出,在控制组中,肾脏作为PSMA较高表达的器官,配合物均在2h时表现出了高的肾脏摄取,而其它非靶组织和器官的摄取很低,血液清除快。提前30min注射抑制剂ZJ-43后,肾脏摄取明显降低,抑制效果显著,表明配合物与PSMA特异性结合。
在上述配合物中,选择99mTc-GLPH-EDDA和99mTc-GLPH-PSA进行荷22Rv1瘤BALB/c雄性裸鼠的生物评价。提前30min给荷22Rv1瘤BALB/c雄性裸鼠注射500μg ZJ-43,然后再注射0.1mL配合物溶液(0.185MBq,15pmol)。给药2h后处死小鼠,取其肾脏、心、肺、血、肌肉等组织和脏器,擦净后称重,并利用γ-Counter计数器测其放射性计数,计算各组织和脏器的每克百分注射剂量(%ID/g)。
表11 99mTc-GLPH-EDDA在荷22Rv1瘤BALB/c雄性裸鼠中生物分布结果(2h p.i.,n=4,%ID/g)
表12 99mTc-GLPH-PSA在荷22Rv1瘤BALB/c雄性裸鼠中生物分布结果(2h p.i.,n=4,%ID/g)
22Rv1肿瘤是PSMA中等程度表达的肿瘤模型,荷瘤动物实验结果表明,99mTc-GLPH-EDDA和99mTc-GLPH-PSA配合物在肿瘤中有较高的摄取、肿瘤/肌肉以及肿瘤/血比值,提前30min注射抑制剂ZJ-43后,肿瘤摄取明显降低,抑制效果明显,说明其与PSMA是特异性靶向结合。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,除了本发明涉及到的含L-脯氨酸修饰的谷氨酸-脲衍生物外,含D-脯氨酸修饰的谷氨酸-脲衍生物以及相应共配体M为N-三(羟甲基)甲基甘氨酸(Tricine)和乙二胺-N,N'-二乙酸(EDDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠(TPPTS)、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯-3-磺酸钠(TPPMS)、N-三(羟甲基)甲基甘氨酸(Tricine)和2-(吡啶-4-基)乙酸(PA)、N-三(羟甲基)甲基甘氨酸(Tricine)和烟酸(NIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和异烟酸(ISONIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,5-吡啶二羧酸(PDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和3-吡啶磺酸(PSA)时进行放射性核素标记后得到的放射性制剂均属于本发明要求保护的范围。此外,将含L-脯氨酸或D-脯氨酸修饰的谷氨酸-脲衍生物和共配体M为N-三(羟甲基)甲基甘氨酸(Tricine)和3,3'-(苯基膦二基)二(苯-1-磺酸)二钠(TPPDS)、N-三(羟甲基)甲基甘氨酸(Tricine)和葡庚糖酸盐、N-三(羟甲基)甲基甘氨酸(Tricine)和葡糖胺、N-三(羟甲基)甲基甘氨酸(Tricine)和甘露糖醇、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯甲酸时进行放射性核素标记后得到的放射性制剂也属于本发明要求保护的范围。
Claims (5)
2.一种放射性制剂,其特征在于,所述放射性制剂包含用放射性核素标记的权利要求1所述的含L-脯氨酸修饰的谷氨酸-脲衍生物。
3.根据权利要求2所述的放射性制剂,其特征在于,所述放射性核素为99mTc、99Tc、94mTc、94Tc、52Mn、186Re或188Re。
5.权利要求2-4任一项所述的放射性制剂在前列腺癌诊断领域和/或肿瘤治疗领域制备肿瘤显像剂中的应用。
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CN114456227A (zh) * | 2022-01-19 | 2022-05-10 | 北京师范大学 | 锝-99m标记含D-脯氨酸甘氨酸多肽修饰的FAPI衍生物及制备方法和应用 |
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